Abstract: Core C In vivo efficacy testing is an essential part of medical countermeasure (MCM) development. For hemorrhagic fever viruses (HFV), where human clinical trials are difficult or unethical to conduct, the Food and Drug Administration (FDA) instituted the animal rule. Licensure via the FDA animal rule requires efficacy testing in at least two surrogate animal models of human disease. In support of overall Prometheus objectives, Core C will execute in vivo efficacy testing of antibody-based MCMs derived from Projects I, II, and III in rodent and nonhuman primate (NHP) models of filovirus, hantavirus, and nairovirus disease. Rodent models of ebolavirus, hantavirus, and nairovirus disease will serve as the first in vivo screening mechanism to down-select monoclonal antibody (mAb)-based MCMs for further assessment in higher animal models. Hamster models of hantavirus infection and mouse models of CCHFV infection will be utilized to evaluate newly discovered mAbs from Project I and down-select lead mAbs for NHP testing. Core C will evaluate in vivo efficacy of mAbs with altered Fc effector functions from Project II in rodent models of disease to identify mAb modifications with optimal in vivo potency. The prophylactic efficacy of Project III DMAbs expressing ebolavirus, hantavirus, and CCHFV-specific mAbs will be evaluated first in rodent models of disease and lead DMAbs will be tested in NHPs. In vivo efficacy results from all Core C efforts will be funneled into Projects I, II, and III and Cores A and B for identification of lead mAb cocktails and/or DMAb constructs for advanced development discussions.